A growing body of evidence suggests that geographically diverse women who are high risk of HIV infection through sexual contact may be protected from infection as a result of acquired immunity to the virus. Several studies have now demonstrated both HIV-specific cellular and humoral immune responses in the genital tract secretions of highly exposed, uninfected women. A better understanding of these potentially protective responses may aid in HIV preventive vaccine development, and may provide insight into the possible utility of targeting the genital tract as a route of immunization against HIV transmission in future vaccine trials. This proposal has two aims. The first aim is to characterize and compare HIV-specific humoral and cellular responses in the genital tract tracts of existing cohorts of women. This proposal has two aims. The first aim is to characterize and compare HIV-specific humoral and cellular responses in the genital tracts of existing cohorts of women: 64 uninfected women from the Project WISH/CDC Vision study who are highly exposed to HIV through sexual transmission; 33 uninfected women (IDUs) from the COIP/NIDA Needle Exchange study who have high parental exposure and low sexual exposure to HIV; 33 women have little or no risk of exposure to HIV from the UIC Medical Center GYN clinic; and, 33 HIV-infected women from the Chicago WIHS study. The second study aim is to measure the HIV-specific humoral and cellular responses in the genital tracts of the women in participating in HIV vaccine efficacy trials. Thirty women will be recruited from the ongoing VaxGen VAX0004 efficacy trials that are ongoing at Project WISH. Project WISH will recruit two hundred five women from the NIAID HVTN 301 vaccine trials that are scheduled to begin in June, 2001. CVLs, cervical wicks, serum, and risk assessments will be collected from all women participating in these mucosal immunity studies. A cytobrush will be used to collect cervical cells from a subset of women. Two samples will be collected at six-month intervals from the women participating in the Aim 1 studies. Sample collection for the vaccine studies in Aim 2 will coincide with the vaccination schedule. Proposed measurements of humoral immunity include HIV-specific binding, neutralizing and ADCC antibodies. Proposed measurement of cellular immunity include CTL and CD4 lymphoproliferation and chemokine receptor expression.